GESTATIONAL DIABETES

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ORIGINAL PROF-3019

DOI: 10.17957/TPMJ/15.3019

GESTATIONAL DIABETES;

TO COMPARE THE EFFICACY OF METFORMIN WITH INSULIN IN

DIABETES MELLITUS IN TERMS OF FETOMATERNAL OUTCOME
Tayyaba Majeed1, Rabia Adnan2, Irum Mubshar3, Hamis Mahmood4, Kanwal Saba5,
Sardar Fakhar Imam6, Muhammad Al-Fareed Zafar7, Mulazim Hussain Bukhari8
1. Professor of Gynae & Obs.
Central Park Medical & Dental
College, Lahore
2. Assistant Professor Gynae & Obs.
Lady Willingdon Hospital, Lahore.
3. Gynaecologist
Lady Willingdon Hospital, Lahore.
4. Consultant Surgeon
LM&DC Lahore
5. Demonstrator Pathology
Fatima Jinnah Medical University
for Women Lahore.
6. Vice Chancllor / Prof. of Medicine
Fatima Jinnah Medical University
for Women Lahore.
7. Professor of Gynae & Obs.
Punjab Medical College /
Allied Hospital Faisalabad.
8. Professor of Pathology
Head of Department
Punjab Medical College /
Allied Hospital Faisalabad.

ABSTRACT Objectives: To compare the efficacy of Metformin with insulin in gestational

diabetes mellitus in terms of fetomaternal outcome. Study Deign: Randomized clinical
trial study. Setting: Lady Aitchison Hospital Lahore. Period: January 2014 to March 2015.
Methodology: Total 500 pregnant females with GDM were included in the study through nonprobability, consecutive sampling. Patients were divided into 2 equal groups (A: B). Patients
in group A were given tablet metformin 500 mg by oral route and group B was administrated
regular injection Insulin by subcutaneous route. Results: The mean age of females was
32.146.13 years. The mean gestational age was 31.073.8 weeks. There were 78 (15.6%)
females who had 0 parity, 107 (21.4%) females had parity 1, 175 (35%) females had parity
2, 95 (19%) females had parity 3, 33 (6.6%) females had parity 4 and 12 (2.4%) females
had parity 5.There were 54 (10.8%) cases had PTB, out of which 12 (4.8%) had PTB with
metformin while 42 (16.8%) had PTB with insulin. There were 115 (23%) neonates required
NICU admission, out of which 37 (14.8%) neonates with metforminand78 (31.2%) neonates
with insulin. There were 87 (17%) neonates who had neonatal hypoglycemia, out of which
23 (9.2%) neonates with metformin and64 (25.6%) neonates with insulin. The difference was
significant between both groups for all fetal outcomes (P<0.05). Conclusion: The metformin
is more effective in preventing adverse fetal and maternal outcome as compared to insulin.

Correspondence Address:
Dr. Mulazim Hussain Bukhari
mulazim.hussain@gmail.com

Key words:

Article received on:

10/07/2015
Accepted for publication:
17/08/2015
Received after proof reading:
12/10/2015

Article Citation: Majeed T, Adnan R, Mubshar I, Mahmood H, Saba K, Imam SF, Zafar MAF,
Bukhari MH. Gestational diabetes; to compare the efficacy of metformin with
insulin in diabetes mellitus in terms of fetomaternal outcome. Professional
Med J 2015;22(10):1298-1303. DOI: 10.17957/TPMJ/15.3019

Gestational diabetes mellitus, metformin, insulin, preterm birth, neonatal

intensive care unit admission, and neonatal hypoglycemia

INTRODUCTION
Gestational diabetes mellitus (GDM), defined as
any degree of glucose intolerance with appearance or first detection during pregnancy, affects
2-10% pregnancies in the United States.1,2 Women with gestational diabetes have a 35-60% risk of
developing DM over next 10-20 years.1
Hyperglycemia in pregnancy results in both maternal and fetal complications. Maternal complications consist of hypertension, preeclampsia,
increased risk of cesarean delivery, and long term
risk of diabetes mellitus. Fetal complications include macrosomia, neonatal hypoglycemia, polycythemia, increased perinatal mortality, congenital malformation, hyperbilirubinemia, respiratory
distress syndrome, and hypocalcaemia. Long
term effects of macrosomia include increased risk
of glucose intolerance, diabetes, and obesity in
Professional Med J 2015;22(10): 1298-1303.

childhood.3
The risk factors, for GDM, which should be noted
at the first prenatal visit, include obesity, age more
than 25 years, past history of gestational diabetes,
first-degree relative with diabetes, badobstetrical
history, Polycystic ovarian syndrome and certain
ethnic groups.
Women having insulin resistance are at risk for
developing GDM. This leading to GDM is dueto
changes of late pregnancy. In pregnancy, human
placental lactogen and tumor-necrosis factor alpha induce changes in the insulin receptor and
in post-receptor signaling. Various changes at the
cellular level appear to be involved in reducing
glucose uptake in skeletal muscle tissue.5
The blood sugar levels should be optimized to
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decrease the incidence of fetomaternal complications. The previous study has shown thataggressive management in women with GDMreduced
birth weight and macrosomia in infants bornto
mothers who were exposed to the intervention
compared with women who had received routine
care.6 Therefore, measures such as dietary modification, exercise, oral hypoglycemic agents, and
insulin are imperative to reduce the complications.7
When the above-mentioned measures do not
fulfill the criteria to control blood glucose levels
in pregnant women, the use of subcutaneous insulin therapy is the standard approach for management of GDM.8,9,10 However, insulin use has
its own set of problems including multiple daily
injections, the risk of hypoglycemia and maternal
weight gain.11 It needs to be altered depending
on the patients weight and height, glucose levels and activity levels.12 The issues relating to patients education and compliance as well as the
cost of insulin should be considered. These arguments place oral hypoglycemic therapy into
favors for women with GDM,.13 However, it is
important to take into account fetomaternal impact of oral hypoglycemic agentsfor the women
with GDM. Metformin, which is used for T2D, is
a foremost choice. Metformin has been found to
have a transplacental transfer rate of 1016%14,15
this raises possible concerns about risks of fetal
anomalies, and undesirable effects for mothers
and the newborns after delivery limiting its role
The safety and use of Metformin in pregnancy is under consideration. But the inferences
drawn from variety of trials, which are underpowered,16,17,18,19 lack the ability to define the relative
risks and benefits ofmetformin for GDM.
The rationale of this study was to compare the
efficacy of metformin with insulin in terms of fetomaternal outcome in gestational diabetes mellitus. There is variability in the literature that is published internationally. The study results may or
may not differ from international data due to poor
compliance and genetic variation from patient to
patient, in the light of which new suggestions will
Professional Med J 2015;22(10): 1298-1303.

be made for the liberal use of metformin in population and to minimize the use of parenteral therapy (insulin).
OBJECTIVE
To compare the outcome of Metformin with insulin
in gestational diabetes mellitus.
PATIENTS AND METHODS
This randomized controlled trial study was carried
out on 500 pregnant women with GDM admitted
in the antenatal ward of Lady Aitchison Hospital
from Jan 2014 to March 2015. Written informed
consent was obtained. The women were included
in the study through non-probability, consecutive
sampling.
Demographic information on all variables included; patients age, gestational age, body mass index and maternal weight gain during pregnancy
were noted. The patients were divided in to two
equal groups (A & B) by randomization. Patients
in the group A were given tablet metformin 500mg
by oral route and group B was administrated injection regular insulin by subcutaneous route.
Maternal BSL (2 levels i.e. BSF, 1 hour post prandial) were done hospital laboratory until delivery
and dose of metformin and insulin was adjusted
according to BSL. Fetal monitoring was done by
ultrasound in the third trimester for fetal weight
evaluation. The women between 20-45 years of
age and GDM, gestational more than 20 weeks
were included in the study and women who were
known diabetic, with history of recent myocardial infarction and twin pregnancy were excluded
from the study.
The women were evaluated for outcome measures
which were Preterm delivery (It will be considered
if birth is at <37 gestational weeks on LMP) and
Neonatal Hypoglycemia (It was assessed by serum blood glucose level (two or more neonatal
glucose values <2.6 mmol per liter [46.8 mg per
deciliter] within 24 hour of birth), and all the information was recorded on Performa. The data was
analyzed by t and chi square depending on the
nature of the variable. A p value of 0.05 was
considered statistically significant.
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RESULTS
We conducted this trial with 500 females included in the study with the mean age of 32.146.13
years. The mean gestational age was 31.073.8
weeks 24-38weeks). There were 78 (15.6%) females who had 0 parity, 107 (21.4%) females had
parity 1, 175 (35%) females had parity 2, 95 (19%)
females had parity 3, 33 (6.6%) females had parity 4 and 12 (2.4%) females had parity 5.
The mean weight of females before treatment
was 70.1810.96 kg, which was increased to
73.1411.49 kg after treatment. The overall mean
change in weight of females was 2.961.90kg.
There were 114 (22.8%) females had normal BMI,
213 (42.6%) were overweight and 173 (34.6%)
were obese.
With metformin, the mean weight of females before treatment was 69.6210.93kg, which was
increased to 72.0511.73 kg after treatment,
with the mean weight change of 2.441.81
kg. With insulin, the mean weight of females
was 70.7510.98kg, which was increased to
74.2411.16 kg, with the mean weight change of
3.491.84 kg. Thus after treatment the difference
was significant (P<0.05).
There were 54 (10.8%) cases had preterm birth,
out of which 12 (4.8%) with metformin and 42
(16.8%) with insulin (Fig-1, Table-I).
There were 115 (23%) neonates required NICU
admission, out of which 37 (14.8%) with metformin while 78 (31.2%) with insulin (Fig-2, Table-II).

Fig-I. (Distribution of preterm birth)

Study group

Total

Metformin

Insulin

Yes

12 (4.8%)

42
(16.8%)

54
(10.8%)

No

238
(95.2%)

208
(83.2%)

446
(89.2%)

250
(100%)

250
(100%)

500
(100%)

PTB

Total

Table-I. (Comparison of preterm birth in both study

groups)
Study group

NICU
admission

Total

Metformin

Insulin

Yes

37
(14.8%)

78
(31.2%)

115
(23%)

No

213
(85.2%)

172
(68.8%)

385 (77%)

250
(100%)

250
(100%)

500
(100%)

Total

Table-II. (Comparison of NICU admission in both

study Of neonates)

There were 87 (17%) neonates had neonatal

hypoglycemia, out of which 23 (9.2%) with metformin while64 (25.6%) with insulin (Fig-3, Table-III).
There was significant difference between both
groups (P<0.05).
Fig-2. Distribution of NICU admission

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Study group

Neonatal
hypoglycemia
Total

Total

Metformin

Insulin

Yes

23
(9.2%)

64
(25.6%)

87
(17%)

No

227
(90.8%)

186
(74.4%)

413
(83%)

250
(100%)

250
(100%)

500
(100%)

Table-III. (Comparison of neonatal hypoglycemia)

Fig-3. Distribution of Neonatal hypoglycemia

in both study groups

DISCUSSION
In this trial we observed that the mean age of
32.146.13 years. The mean gestational age
was 31.073.8 weeks 24-38weeks). There were
78 (15.6%) females who had 0 parity, 107 (21.4%)
females had parity 1, 175 (35%) females had parity 2, 95 (19%) females had parity 3, 33 (6.6%)
females had parity 4 and 12 (2.4%) females had
parity 5.

ence was significant (P<0.05). In a randomized

trial by Rowan, mean weight gain was 0.940.3
with metformin and 2.72+0.4 with insulin. (20)But
another study by Tertti reported that weight gain
was 0.42.9kg and 2.03.3kg with metformin
and insulin.16
There were 54 (10.8%) cases had preterm birth,
out of which 12 (4.8%) with metformin and 42
(16.8%) with insulin. There were 115 (23%) neonates required NICU admission, out of which
37 (14.8%) with metformin while78 (31.2%) with
insulin. There were 87 (17%) neonates had neonatal hypoglycemia, out of which 23 (9.2%) with
metformin while64 (25.6%) with insulin. There
was significant difference between both groups
(P<0.05).
In the study by Rowan PTB was observed in 0%
cases with metformin and 10% with insulin, NICU
admission in 6% with metformin and 19% with
insulin, hypoglycemia in 9% with metformin and
18% with insulin.(20) The study by Terstti supported our results and reported that with metformin,
PTB occurred in 4.4% cases, NICU admissions
in 42.2% cases and neonatal hypoglycemia in
34.1% cases. With insulin, PTB occurred in 11.1%
cases, NICU admissions in 62.2% cases and neonatal hypoglycemia in 57.8% cases. However, the
difference was insignificant (P>0.05).16

The mean weight of females before treatment

was 70.1810.96 kg, which was increased to
73.1411.49 kg after treatment. The overall mean
change in weight of females was 2.961.90kg.
There were 114 (22.8%) females had normal BMI,
213 (42.6%) were overweight and 173 (34.6%)
were obese.

When compared with insulin, metformin was associated with less maternal weight gain (pooled
mean difference 1.14 kg (95% CI 2.22 to
0.06)), lower gestational age at delivery (pooled
mean difference 0.16 weeks (0.30 to 0.02)),
and more preterm birth (pooled risk ratio 1.50
(1.04 to 2.16)). A trend was observed towards a
lower rate of any neonatal hypoglycaemia (pooled
risk ratio 0.78 (0.60 to 1.01)).21

With metformin, the mean weight of females before treatment was 69.6210.93kg, which was
increased to 72.0511.73 kg after treatment,
with the mean weight change of 2.441.81
kg. With insulin, the mean weight of females
was 70.7510.98kg which was increased to
74.2411.16 kg, with the mean weight change
of 3.491.84 kg. Thus after treatment the differ-

In Tertti study NICU admission was 18% with

metformin and 21% insulin group, hypoglycemia
in 34% and 57% with metformin and insulin respectively.16One more study reported contradictory results as reported in our study. It was observed that PTB was 12.1% with metformin and
7.6% with insulin and the statistical difference was

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obtained as significant (P<0.05).(21) In another

cohort of women studied by Rowan and Hughes
with diabetes, maternal/fetal outcomes were as
good in women using metformin as those on insulin alone, even though women in the metformin
group were at higher risk of poor outcomes.22

whole staff of Department of Pathology and Obstetrics and gynecology Lady Aitchison Hospital,
Lahore on their cooperation during collection and
analysis of the data.
Copyright 17 Aug, 2015.

In a study conducted by Niromanesh etal the maternal weight gain was reduced in the metformin
group (P<0.001). Two groups were comparable
according to neonatal and obstetric complications (P>0.05).23

1. Health UDo, Services H. National Diabetes Information Clearinghouse (NDIC). National Diabetes Statistics. 2011.

Mesdaghinia and colleagues conducted a prospective randomized trial in which it was seen that
maternal weight gain during pregnancy, preterm
labor and hospitalization of infants were higher
in in insulin group. But there were no significant
statistical differences between the two groups regarding neonatal hypoglycaemia.24
In a study conducted by Spaulonci et al it was
seen that women using metformin had less weight
gain and lower frequency of neonatal hypoglycemia as compared to those using insulin.25A recent
study has indicated a lesser maternal weight gain
but higher incidence of preterm labor with metformin.26
CONCLUSION
It is concluded that metformin is more effective in
controlling blood glucose and prevent adverse fetal outcome as compared to insulin and we have
proved this through this randomized trial. Thus in
future we can recommend metformin instead of
insulin for control of GDM in future as we have got
local magnitudes which will help us in implementation of metformin and will minimize the use of
the use of parenteral therapy i.e. insulin.
Authorship: TM was the principal researcher
and collected the data, RA deigned the research
Protocol, IM and ZM helped in designing the research protocol, HM gave the computer help, KS
did the statistical analysis, SFI and SFZ helped is
writing and finalizing the manuscript.
Acknowledgement.

We are thankful for the

Professional Med J 2015;22(10): 1298-1303.

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Ebeling T, et al. (2011)Metformin should be considered in the treatment of gestational diabetes: aprospective randomised study. BJOG 118: 880885.
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AUTHORSHIP AND CONTRIBUTION DECLARATION

Sr. #

Author-s Full Name

Contribution to the paper

Tayyaba Majeed

Rabia Adnan

Irum Majeed

Hamis Mahmood

Principal researcher and

collection of data
Designed the research
Protocol
Helped in designing the
research protocol
Give the computer help

Kanwal Saba

Did the statistical analysis

Sardar Fakhar Imam

Muhammad Al-Fareed Zafar

Mulazim Hussain Bukhari

Helped is weiting and

finalizing the manuscript
Helped is weiting and
finalizing the manuscript
Supervised the research

Professional Med J 2015;22(10): 1298-1303.

Author=s Signature

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